Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall, et al., Curr. Opin. Immunol., 6:865-873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca2+])1, granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
There are four classes of chemokines, CXC (xcex1), CC (xcex2), C(xcex3), and CX3C (xcex4), depending on whether the first two cysteines are separated by a single amino acid (C-X-C), are adjacent (C-C), have a missing cysteine pair (C), or are separated by three amino acids (CXC3). The xcex1-chemokines, such as interleukin-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-1) are chemotactic primarily for neutrophils and lymphocytes, whereas xcex2-chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Nature, 381:661-666 (1996)). The C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al., Science, 266:1395-1399 (1994)) while the CX3C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al., Nature, 385:640-644 (1997).
Chemokines bind specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15:159-165 (1994)) termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated heterotrimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least twelve human chemokine receptors that bind or respond to xcex2-chemokines with the following characteristic pattern: CCR1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) MIP-1xcex1, MIP-1xcex2, MCP-3, RANTES (Ben-Barruch, et al., J. Biol. Chem., 270:22123-22128 (1995); Neote, et al., Cell, 72:415425 (1993)); CCR2A and CCR2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Axe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR2Axe2x80x9d) MCP-1, MCP-3, MCP-4; CCR3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) eotaxin, RANTES, MCP; (Ponath, et al., J. Exp. Med., 183:2437-2448 (1996)); CCR4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) TARC, MDC (Imai, et al., J. Biol. Chem., 273:1764-1768 (1998)); CCR5 (or xe2x80x9cCKR-5xe2x80x9d or xe2x80x9cCC-CKR-5xe2x80x9d) MIP-1xcex1, RANTES, MIP-1xcex2 (Sanson, et al., Biochemistry, 35:3362-3367 (1996)); CCR6 MIP-3 alpha (Greaves, et al., J. Exp. Med., 186:837-844 (1997)); CCR7 MIP-3 beta and 6Ckine (Campbell, et al., J. Cell. Biol., 141:1053-1059(1998)); CCR8 I-309, HHV8 vMIP-I, HHV-8 vMIP-II, MCV vMCC-I (Dairaghi, et al., J. Biol. Chem., 274:21569-21574 (1999)); CCR9 TECK (Zaballos, et al., J. Immunol., 162:5671-5675 (1999)), D6 MIP-1 beta, RANTES, and MCP-3 (Nibbs, et al., J. Biol. Chem., 272:32078-32083 (1997)), and the Duffy blood-group antigen RANTES, MCP-1 (Chaudhun, et al., J. Biol. Chem., 269:7835-7838 (1994)).
Chemokine receptors, such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX3CR1, and XCR1 have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
The CXCR3 chemokine receptor is expressed primarily in T lymphocytes, and its functional activity can be measured by cytosolic calcium elevation or chemotaxis. The receptor was previously referred to as GPR9 or CKR-L2. Its chromosomal location is unusual among the chemokine receptors in being localized to Xq13. Ligands that have been identified that are selective and of high affinity are the CXC chemokines, IP10, MIG and ITAC.
The highly selective expression of CXCR3 makes it an ideal target for intervention to interrupt inappropriate T cell trafficking. The clinical indications for such intervention are in T-cell mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and type I diabetes. Inappropriate T-cell infiltration also occurs in psoriasis and other pathogenic skin inflammation conditions, although the diseases may not be true autoimmune disorders. In this regard, up-regulation of IP-10 expression in keratinocytes is a common feature in cutaneous immunopathologies. Inhibition of CXCR3 can be beneficial in reducing rejection in organ transplantation. Ectopic expression of CXCR3 in certain tumors, especially subsets of B cell malignancies indicate that selective inhibitors of CXCR3 will have value in tumor immunotherapy, particularly attenuation of metastasis.
In view of the clinical importance of CXCR3, the identification of compounds that modulate CXCR3 function represents an attractive avenue into the development of new therapeutic agents. Such compounds are provided herein.
The present invention provides compounds which are useful in the treatment or prevention of certain inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The compounds provided herein have the general formula (I): 
wherein X represents a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(R5)(R6)xe2x80x94, xe2x80x94C(R5)xe2x95x90, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94Nxe2x95x90; Z represents a bond, xe2x80x94Nxe2x95x90, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R17)xe2x80x94 or xe2x80x94C(R7)xe2x95x90, with the proviso that X and Z are not both a bond; L represents a bond, C(O)xe2x80x94(C1-C8)alkylene, (C1-C8)alkylene or (C2-C8)heteroalkylene; Q represents a bond, (C1-C8)alkylene, (C2-C8)heteroalkylene, xe2x80x94C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94N(R8)C(O)xe2x80x94, xe2x80x94CH2COxe2x80x94, xe2x80x94CH2SOxe2x80x94 or xe2x80x94CH2SO2xe2x80x94, and optionally L and Q can be linked together to form a 5- or 6-membered heterocyclic group having from 1 to 3 heteroatoms. The symbols R1 and R2 independently represent H, (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl or heteroaryl, or optionally are combined to form a 3 to 8-membered ring having from 0 to 2 heteroatoms as ring vertices, and optionally R2 and L can be linked together to form a 5- or 6-membered heterocyclic group having from 1 to 4 heteroatoms. The symbol R3 represents hydroxy, (C1-C8)alkoxy, amino, (C1-C8)alkylamino, di(C1-C8)alkylamino, (C2-C8)heteroalkyl, (C3-C9)heterocyclyl, (C1-C8)acylamino, amidino, guanidino, ureido, cyano, heteroaryl, xe2x80x94CONR9R10 or xe2x80x94CO2R11. The symbol R4 represents (C1-C20)alkyl, (C2-C20)heteroalkyl, heteroaryl, aryl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C6)heteroalkyl, aryl(C1-C6)alkyl or aryl(C2-C6)heteroalkyl. The symbols R5 and R6 independently represent H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl or aryl, or optionally R5 and R6 are combined to form a 3- to 7-membered ring. The symbols R7 and R8 independently represent H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl or aryl. The symbols R9, R10 and R11 each independently represent H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl, aryl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C8)heteroalkyl, aryl(C1-C8)alkyl or aryl(C2-C8)heteroalkyl.
Turning next to the ring vertices, Y1, Y2, Y3 and Y4, the symbols Y1 and Y2 independently represent xe2x80x94C(R12)xe2x95x90, xe2x80x94Nxe2x95x90, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94N(R13)xe2x80x94. The symbol Y3 represents N or C wherein the carbon atom shares a double bond with either Z or Y4; and Y4 represents xe2x80x94N(R14)xe2x80x94, xe2x80x94C(R14)xe2x95x90, xe2x80x94Nxe2x95x90 or N(R14)C(R15)(R16)xe2x80x94. In the above groups, the symbol R12 represents H, halogen, hydroxy, amino, alkylamino, dialkylamino, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl and aryl, or optionally when Y1 and Y2 are both xe2x80x94C(R12)xe2x95x90 the two R12 groups can be combined to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; or optionally when Y1 is xe2x80x94C(R12)xe2x95x90 and X is xe2x80x94C(R5)xe2x95x90 or xe2x80x94C(R5)(R6)xe2x80x94, R12 and R5 can be combined to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring. Additionally, the symbol R13 represents H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl, aryl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C8)heteroalkyl, aryl(C1-C8)alkyl or aryl(C2-C8)heteroalkyl. The symbol R14 represents (C1-C8)alkyl, (C2-C8)heteroalkyl, aryl(C1-C8)alkyl, aryl(C2-C8)heteroalkyl, heteroaryl(C1-C8)alkyl, heteroaryl(C2-C8)heteroalkyl, heteroaryl and aryl; R15 and R16 are independently selected from H, (C1-C8)alkyl and (C2-C8)heteroalkyl; and R17 is selected from H, (C1-C8)alkyl, (C2-C8)heteroalkyl, heteroaryl, aryl, heteroaryl(C1-C6)alkyl, heteroaryl(C2-C8)heteroalkyl, aryl(C1-C8)alkyl and aryl(C2-C8)heteroalkyl, or optionally when Y2 is xe2x80x94C(R12)xe2x95x90 or xe2x80x94N(R13)xe2x80x94, R17 can be combined with R12 or R13 to form a substituted or unsubstituted 5- to 6-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; with the proviso that when the Y3-containing ring system is a quinazolinone or quinolinone ring system, and R4xe2x80x94Qxe2x80x94 is substituted or unsubstituted (C5-C15)alkyl, then R3xe2x80x94Lxe2x80x94 is other than substituted or unsubstituted (C2-C8)alkylene or a substituted or unsubstituted (C2-C8)heteroalkylene attached to xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are independently selected from the group consisting of hydrogen and (C1-C8)alkyl, or optionally are combined with the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered ring.
Unless otherwise indicated, the compounds provided in the above formula are meant to include pharmaceutically acceptable salts and prodrugs thereof.
The present invention also provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable excipient or carrier.
The present invention further provides methods for the treatment or prevention of an inflammatory or immune condition or disorder, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of a compound of formula I.
The present invention also provides methods for the treatment or prevention of a condition or disorder mediated by the CXCR3 chemokine receptor, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of a compound of formula I.
The present invention also provides methods for the modulation of CXCR3, comprising contacting a cell with a compound of formula I.
The present invention further provides methods for the modulation of CXCR3, comprising contacting a CXCR3 protein with a compound of formula I.